Synergistic combination

ABSTRACT

The invention relates to the combined administration of PDE inhibitors and β2 adrenoceptor agonists for the treatment of respiratory disorders.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to the combination of certain known activecompounds for therapeutic purposes.

The substances used in the combination according to the invention areknown active compounds from the PDE inhibitors class and activecompounds from the β₂ adrenoceptor agonists class. Their combined use inthe sense according to the invention for therapeutic purposes has notyet been described in the prior art.

DESCRIPTION OF THE INVENTION

It is the object of the present invention to make available respiratorytract therapeutics which fulfill the following conditions:

-   -   Good antiinflammatory action    -   Marked bronchorelaxation and -dilatation    -   Good oral availability, at least with respect to the PDE        inhibitor    -   Minor side effects    -   Good suitability for long-term therapy    -   Favorable influence on bronchial hyperreactivity.

It has now been found that the combined use of a PDE inhibitor which canbe used as a respiratory tract therapeutic and of a β₂ adrenoceptoragonist outstandingly fulfills the abovementioned conditions.

The invention thus relates to the combined use of a PDE inhibitor whichcan be used as a respiratory tract therapeutic and a β₂ adrenoceptoragonist in the treatment of respiratory tract disorders.

PDE inhibitors which can be used as respiratory tract therapeutics inthe sense of the present invention are those compounds which slow thebreakdown of cyclic AMP (cAMP) or cyclic GMP (cGMP) by inhibition of thephosphodiesterases, which can lead to a relative increase in theintracellular concentration of cAMP or cGMP.

Possible PDE inhibitors within the meaning of the present invention areprimarily those substances which are to be considered part of the PDE4inhibitor class and those substances which can be designated as mixedtypes of PDE3/4 inhibitors. By way of example, those PDE inhibitors maybe mentioned which are described or claimed in the following patentapplications and patents: DE 1545687, DE 2028869, DE 2123328, DE2315801, DE 2402908, DE 2413935, DE 3900233, EP 0103497, EP 0139464, EP0158380, EP 0163965, EP 0335386, EP 0389282, EP 0428302, EP 0435811, EP0459505, EP 0470805, EP 0490823, EP 0506194, EP 0511865, EP 0527117, EP0557016, EP 0626939, EP 0664289, EP 0671389, EP 0685474, EP 0685475, EP0685479, EP 0736532, EP 0738715, EP 0748805, EP 0763534, EP 0816357, EP0819688, EP 0819689, EP 0832886, EP 0834508, EP 0848000, JP 92234389, JP94329652, JP 95010875, JP 98072415, JP 98147585, U.S. Pat. No. 5703098,U.S. Pat. No. 5739144, WO 9117991, WO 9200968, WO 9212961, WO 9307146,WO 9315044, WO 9315045, WO 9318024, WO 9319068, WO 9319720, WO 9319747,WO 9319749, WO 9319751, WO 9325517, WO 9402465, WO 9412461, WO 9420455,WO 9422852, WO 9427947, WO 9501338, WO 9501980, WO 9503794, WO 9504045,WO 9504046, WO 9505386, WO 9508534, WO 9509623, WO 9509624, WO 9509627,WO 9509836, WO 9514667, WO 9514680, WO 9514681, WO 9517392, WO 9517399,WO 9519362, WO 9520578, WO 9522520, WO 9524381, WO 9527692, WO 9535281,WO 9535283, WO 9535284, WO 9600218, WO 9601825, WO 9606843, WO 9611690,WO 9611917, WO 9612720, WO 9631486, WO 9631487, WO 9635683, WO 9636595,WO 9636596, WO 9636611, WO 9636625, WO 9636638, WO 9638150, WO 9639408,WO 9640636, WO 9703967, WO 9704779, WO 9705105, WO 9708143, WO 9709345,WO 9712895, WO 9718208, WO 9719078, WO 9720833, WO 9722585, WO 9722586,WO 9723457, WO 9723460, WO 9723461, WO 9724117, WO 9724355, WO 9725312,WO 9728131, WO 9730999, WO 9731000, WO 9732853, WO 9735854, WO 9736905,WO 9743288, WO 9744036, WO 9744322, WO 9747604, WO 9748697, WO 9804534,WO 9805327, WO 9806692, WO 9806704, WO 9807715, WO 9808828, WO 9808830,WO 9808841, WO 9808844, WO 9809946, WO 9809961, WO 9811113, WO 9814448,WO 9818796, WO 9821208, WO 9822453, WO 9845268, WO 9855481, WO 9856756,WO 9905111, WO 9905112, WO 9505113, WO 9906404 and WO 9918095. Those PDEinhibitors are to be emphasized which are claimed in the patentapplications or patents EP 0393500, EP 0510562, EP 0553174, WO 9501338,WO 9603399, WO 9636625, WO 9636626, WO 9735854, WO 9821208, WO 9831674,WO 9840382, WO 9855481, WO 9905111, WO 9905112, WO 9905113, WO 9931071and WO 9931090. Substances having good oral availability are preferredhere.

Exemplary PDE inhibitors are shown on the following pages with the aidof their formulae:

No hydrogen atoms are indicated in the above formulae. —O isaccordingly-OH, —N is NH₂. Methyl groups, e.g. on the oxygen atoms, areindicated by lines.

PDE inhibitors to be emphasized which are selected from theabovementioned compounds and which may be mentioned are the activecompounds arofylline, atizoram, AWD-12-281, BAY-19-8004, benafentrine,BYK-33043, CC-3052, CDP-840, CI-1018, cipamfylline, CP-220629,CP-293121, D-22888, D-4396, D-4418, denbufylline, filaminast, GW-3600,ibudilast, KF-17625, KS-506-G, laprafylline, NA-0226A, NA-23063A,ORG-20241, ORG-30029, PDB-093, pentoxifylline, piclamilast, roflumilast,rolipram, RPR-117658, RPR-122818, RPR-132294, RPR-132703, RS-17597,RS-25344-000, SB-207499, SB-210667, SB-211572, SB-211600, SB-212066,SB-212179, SDZ-ISQ-844, SDZ-MNS-949, SKF-107806, SQ-20006, T-2585,T-440, tibenelast, tolafentrine, UCB-29646, V-11294A, YM-58997, YM-976and zardaverine.

The compounds preferred from the group of the abovementioned PDEinhibitors are arofylline, cipamfylline, D-4418, filaminast, ibudilast,laprafylline, ORG-20241, piclamilast, rolipram, SB-207499, tibenelastand V-11294A. The compounds particularly preferred are BYK-33043 and inparticular roflumilast.

β₂ adrenoceptor agonists which may particularly be mentioned are thoseselectively acting substances which only have a slight cardiac actionand therefore are also employed in therapy, in particular in the oraltherapy of respiratory tract disorders. β₂ adrenoceptor agonists whichmay be mentioned are, for example: AR-C68397AA, broxaterol, CHF-1035,HOKU-81, ibuterol, KUL-1248, soterenol, meluadrine, TA-2005, tiaramide,salbutamol, levosalbutamol, tulobuterol, terbutaline, carbuterol,pirbuterol, reproterol, clenbuterol, fenoterol, hexoprenaline,orciprenaline, isoprenaline, formoterol, salmeterol, rimiterol,procaterol, bambuterol, bitolterol and mabuterol. The orally readilyavailable β₂ adrenoceptor agonists such as clenbuterol, orciprenaline,salbutamol, terbutaline, tulobuterol, bambuterol and reproterol arepreferred. Particularly preferred are the so-called long acting β₂adrenoceptor agonists, such as salmeterol.

The PDE inhibitors and the β₂ adrenoceptor agonists can be present assuch or in chemically bonded form. It is understood hereby that theactive compounds mentioned can also be present, for example, in the formof their pharmacologically tolerable salts and/or as solvates (e.g.hydrates), and/or in the form of their N-oxides etc. Suitablepharmacologically tolerable salts here are in particular water-solubleand water-insoluble acid addition salts with acids such as, for example,hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid,sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonicacid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation—depending on whether it is a mono- orpolybasic acid and depending on which salt is desired—in an equimolarquantitative ratio or one differing therefrom. Furthermore, the activecompounds mentioned can also be present as pure enantiomers or asenantiomer mixtures in any mixing ratio.

Respiratory tract disorders which may be mentioned are in particularallergen- and inflammation-induced bronchial disorders (bronchitis,obstructive bronchitis, spastic bronchitis, allergic bronchitis,allergic asthma, bronchial asthma, COPD), which can be treated by thecombination according to the invention also in the sense of a long-termtherapy (if desired with appropriate adjustment of the dose of theindividual components to the needs at the time, for example needssubject to seasonally related variations).

“Combined use” or “combination” within the meaning of the presentinvention is to be understood as meaning that the individual componentscan be administered simultaneously (in the form of a combinationmedicament), more or less simultaneously (from separate pack units) orin succession (directly in succession or else alternatively at arelatively large time interval) in a manner which is known per se andcustomary.

Within the meaning of the present invention, “use” is preferablyunderstood as meaning the oral administration of both active compounds.If only the PDE inhibitor is administered orally, “use” with respect tothe β₂ adrenoceptor agonist is understood in particular as meaningtopical application in inhalatory form. For this, the β₂ adrenoceptoragonist is preferably administered by inhalation in the form of anaerosol, the aerosol particles of solid, liquid or mixed compositionhaving a diameter of 0.5 to 10 μm, advantageously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-drivenjet atomizers or ultrasonic atomizers, but advantageously bypropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from inhalation capsules.

The active compounds are dosed in an order of magnitude customary forthe individual dose, it more likely being possible, on account of theindividual actions, which are mutually positively influencing andreinforcing, to reduce the respective doses on the combinedadministration of the active compounds compared with the norm.Customarily, the β₂ adrenoceptor agonist (depending on potency) isadministered in a dose of, for example, 0.002 to 2.0 mg per day onadministration by inhalation.

Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patient. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®)),and automatic devices emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

In the case of the oral administration of the β₂ adrenoceptor agoniststogether with the PDE inhibitor, which is the preferred administrationform, the β₂ adrenoceptor agonist is administered in a daily dose of,for example, 0.05 to 60 mg. For the PDE inhibitors, it is possible inthe case of oral administration to vary the doses—depending on theactive compound—within a wide range, it being possible, as bounds, tostart from a dose of 1-2000 μg/kg of body weight. In the case of theadministration of the preferred PDE inhibitor roflumilast, the dose isin the range from 2-20 μg/kg of body weight.

The PDE inhibitors to be administered orally are formulated—ifappropriate together with the β₂ adrenoceptor agonists—to givemedicaments according to processes known per se and familiar to theperson skilled in the art. The pharmacologically active compounds areemployed as medicaments, preferably in combination with suitablepharmaceutical excipients or vehicles, in the form of tablets, coatedtablets, capsules, emulsions, suspensions or solutions, the activecompound content advantageously being between 0.1 and 95% and, by theappropriate choice of the excipients and vehicles, it being possible toachieve a pharmaceutical administration form precisely tailored to theactive compound(s) and/or to the desired onset of action (e.g. asustained-release form or an enteric form). Particularly worthy ofmention within the meaning of the combined, oral administration of bothactive compounds according to the invention are oral administrationforms, e.g. tablets or capsules, in which one part of the β₂adrenoceptor agonist and the PDE inhibitor is present in nonsustained-release form and a further, preferably larger part, of the β₂adrenoceptor agonist is present in sustained-release form.

The person skilled in the art is familiar on the basis of his/her expertknowledge with which excipients or vehicles are suitable for the desiredpharmaceutical formulations. In addition to solvents, gel-formingagents, tablet excipients and other active compound carriers, it ispossible to use, for example, antioxidants, dispersants, emulsifiers,antifoams, flavor corrigents, preservatives, solubilizers, colorants orpermeation promoters and complexing agents (e.g. cyclodextrins).

Pharmacology

Model

Late Inflammatory Airway Reaction in theOvalbumin-sensitized/-challenged Brown-Norway Rat

Anti-inflammatory activity of Roflumilast, Pumafentrine (BYK-33043), andSalmeterol was determined in ovalbumin (OVA)-sensitized andOVA-challenged Brown Norway rats. Sensitization was done by simultaneousinjection of Bordetella pertussis suspension i.p. and OVA/AHG suspensions.c. on day 1, 14 and 21. 28 days after start of sensitization,conscious Brown-Norway rats were challenged by inhalation of theaerosolized OVA solution for 1 h (˜20 ml/h). Non-challenged, onlysensitized animals were used as baseline control. The drugs (thoroughlymixed with lactose) or the placebo control (lactose) were administeredintratracheally (i.t.) as dry powders 1 h before OVA-challenge. 48 hlater, OVA-challenged or non-challenged animals were anaesthetized andbronchoalveolar lavage (BAL) was performed using 3×4 ml BAL buffer peranimal. The number of total cells and eosinophils in the BAL fluid, andthe concentration of protein in the cell-free BAL fluid were determined.Drug-induced relative changes were calculated and statistically analyzedby the Jonckheere Terpstra test.

Results Dose % Inhibition of Infiltration/ PDE3/4 [μmol/ Appl.Accumulation [Median/Mean ± SEM] Compound IC50[μmol] kg] Route N Totalcells EOS Protein Roflumilast   >10/0.0007 0.3 it 8 −25 −15 −8 −37.6 ±26.7   −22 ± 25.7 −22.3 ± 25.5 Pumafentrine 0.028/0.007  3 it 8 −19 −2617 −39.1 ± 30.5 −28.5 ± 30.1  23.5 ± 10.6 Salmeterol 3 it 8  19  39 44 6.3 ± 17.9   31 ± 14.8  37.5 ± 16.2 Salmeterol/ 3/0.3 it 8  50   67 **  59 ** Roflumilast  34.5 ± 21.1   61.1 ± 7.9 **   50.8 ± 13.6 **Salmeterol/ 3/3 it 8   56 *   85 **   75 ** Pumafentrine   58.1 ± 12.3 *   83 ± 3.7 **   67.1 ± 11.1 *** p < 0.05,** p < 0.01 v.s. untreated, OVA-challenged control groupsSummary

The PDE inhibitors Roflumilast (PDE4 inhibitor) and Pumafentrine (PDE3>4inhibitor) administered at doses of 0.3 μmol/kg and 3 μmol/kg i.t.,respectively, did not show any significant effects on cell infiltrationand protein accumulation. The negative values obtained (trend:amplification of inflammation) fall into the range of biologicalvariability of the model and therefore, no significance must be attachedto these data.

In contrast, the long-acting β2-adrenergic receptor agonist Salmeterolgiven at a dose of 3 μmol/kg i.t exhibited inhibitory effects on totalcell and eosinophil influx into alveolar space and protein levels in BALfluid. However, the data failed to reach significance.

Co-administration of the PDE inhibitor Roflumilast or Pumafentrine withSalmeterol resulted in synergistic effects compared to administration ofevery compound alone, i.e. both PDE inhibitors combined with the β2agonist displayed a significant inhibition of eosinophilia and reductionof protein concentration in the BAL fluid. The combination of the PDE3/4inhibitor Pumafentrine and Salmeterol was more efficacious on allparameters measured (difference was not significant), and additionally,showed a significant effect on inhibition of total cell influx into thealveolar space.

1-12. (canceled)
 13. A pharmaceutical composition comprising a PDEinhibitor, which is to be administered orally, from the PDE4 or PDE3/4inhibitors group combined with a β₂ adrenoceptor agonist in fixed orfree combination, wherein said PDE inhibitor is selected from the groupconsisting of roflumilast; AWD-12-281; SB-207499; arofylline; ibudilast;a pharmacologically tolerable hydrate, solvate, salt, hydrate of a salt,or solvate of a salt thereof; and an N-oxide of roflumilast, and whereinsaid β₂ adrenoceptor agonist is selected from the group consisting of4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol(salbutamol);(R)-4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol(levosalbutamol); 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)-ethanol(terbutaline);2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-tert-butylaminoethyl)pyridine(pirbuterol);(R*,R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide(formoterol);(±)-4-hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol(salmeterol); and a pharmacologically tolerable hydrate, solvate, salt,hydrate of a salt or solvate of a salt thereof.
 14. The pharmaceuticalcomposition as claimed in claim 13, which is a fixed oral combination.15. The pharmaceutical composition as claimed in claim 13, wherein thePDE inhibitor is a compound selected from the group consisting ofarofylline; ibudilast; SB-207499; and a pharmacologically tolerablehydrate, solvate, salt, hydrate of a salt or solvate of a salt thereof.16. The pharmaceutical composition as claimed in claim 13, wherein thePDE inhibitor is roflumilast or a pharmacologically tolerable hydrate,solvate, salt, hydrate of a salt or solvate of a salt thereof, or anN-oxide of roflumilast.
 17. The pharmaceutical composition as claimed inclaim 13, wherein the PDE inhibitor is roflumilast or apharmacologically tolerable hydrate, solvate, salt, hydrate of a salt orsolvate of a salt thereof, or an N-oxide of roflumilast, and the β₂adrenoceptor agonist is(±)-4-hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol(salmeterol) or a pharmacologically tolerable hydrate, solvate, salt,hydrate of a salt or solvate of a salt thereof.
 18. The pharmaceuticalcomposition as claimed in claim 13, wherein the β₂ adrenoceptor agonistis selected from the group consisting of4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol(salbutamol); 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino) ethanol(terbutaline); and a pharmacologically tolerable hydrate, solvate, salt,hydrate of a salt or solvate of a salt thereof.
 19. The pharmaceuticalcomposition as claimed in claim 13, wherein the PDE inhibitor isselected from the group consisting of arofylline; ibudilast; SB-207499;and a pharmacologically tolerable hydrate, solvate, salt, hydrate of asalt or solvate of a salt thereof, and the β₂ adrenoceptor agonist isselected from the group consisting of4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol(salbutamol); 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)ethanol(terbutaline); and a pharmacologically tolerable hydrate, solvate, salt,hydrate of a salt or solvate of a salt thereof.
 20. The pharmaceuticalcomposition as claimed in claim 13, wherein the PDE inhibitor isroflumilast or a pharmacologically tolerable hydrate, solvate, salt,hydrate of a salt or solvate of a salt thereof, or an N-oxide ofroflumilast, and the β₂ adrenoceptor agonist is selected from the groupconsisting of4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol(salbutamol); 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)ethanol(terbutaline); and a pharmacologically tolerable hydrate, solvate, salt,hydrate of a salt or solvate of a salt thereof.
 21. A method of treatinga respiratory tract disorder in a patient, comprising administering atherapeutically effective amount of a PDE inhibitor from the PDE4- orPDE3/4 inhibitors group in combination with a β₂ adrenoceptor agonist tosaid patient, wherein said PDE inhibitor is administered orally, whereinsaid PDE inhibitor is selected from the group consisting of roflumilast;AWD-12-281; SB-207499; arofylline; ibudilast; a pharmacologicallytolerable hydrate, solvate, salt, hydrate of a salt, or solvate of asalt thereof; and an N-oxide of roflumilast, and wherein said β₂adrenoceptor agonist is selected from the group consisting of4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol(salbutamol);(R)-4-hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl]benzyl alcohol(levosalbutamol); 1-(3,5-dihydroxyphenyl)-2-(tert-butylamino)-ethanol(terbutaline);2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-tert-butylaminoethyl)pyridine(pirbuterol);(R*,R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide(formoterol);(±)-4-hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol(salmeterol); and a pharmacologically tolerable hydrate, solvate, salt,hydrate of a salt or solvate of a salt thereof.
 22. The pharmaceuticalcomposition as claimed in claim 13, wherein the PDE inhibitor isroflumilast or a pharmacologically tolerable hydrate, solvate, salt,hydrate of a salt or solvate of a salt thereof, or an N-oxide ofroflumilast, and the β₂ adrenoceptor agonist is(R*,R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide(formoterol) or a pharmacologically tolerable hydrate, solvate, salt,hydrate of a salt or solvate of a salt thereof.
 23. The pharmaceuticalcomposition as claimed in claim 13, which additionally contains anexcipient selected from the group consisting of propellants,surface-active substances, emulsifiers, stabilizers, preservatives,flavorings, fillers, solvents, gel-forming agents, tablet excipients,antioxidants, dispersants, antifoams, flavor corrigents, solubilizers,colorants or permeation promoters, and complexing agents.
 24. The methodof claim 21, wherein the respiratory tract disorder is anallergen-induced or inflammation-induced bronchial disorder.
 25. Themethod of claim 24, wherein the allergen-induced or inflammation-inducedbronchial disorder is selected from the group consisting of bronchitis,obstructive bronchitis, spastic bronchitis, allergic bronchitis,allergic asthma, bronchial asthma, and COPD.
 26. The method of claim 21,wherein the PDE inhibitor and the β₂ adrenoceptor agonist areadministered simultaneously.
 27. The method of claim 21, wherein the PDEinhibitor and the β₂ adrenoceptor agonist are administered more or lesssimultaneously.
 28. The method of claim 21, wherein the PDE inhibitorand the β₂ adrenoceptor agonist are administered in succession.
 29. Amethod of treating a respiratory tract disorder in a patient, comprisingadministering to said patient a therapeutically effective amount of thepharmaceutical composition as claimed in claim
 17. 30. The method ofclaim 29, wherein the respiratory tract disorder is an allergen-inducedor inflammation-induced bronchial disorder.
 31. The method of claim 30,wherein the allergen-induced or inflammation-induced bronchial disorderis selected from the group consisting of bronchitis, obstructivebronchitis, spastic bronchitis, allergic bronchitis, allergic asthma,bronchial asthma, and COPD.
 32. The method of claim 29, wherein the PDEinhibitor and the β₂ adrenoceptor agonist are administeredsimultaneously.
 33. The method of claim 29, wherein the PDE inhibitorand the β₂ adrenoceptor agonist are administered more or lesssimultaneously.
 34. The method of claim 29, wherein the PDE inhibitorand the β₂ adrenoceptor agonist are administered in succession.
 35. Amethod of treating a respiratory tract disorder in a patient, comprisingadministering to said patient a therapeutically effective amount of thepharmaceutical composition as claimed in claim
 20. 36. The method ofclaim 35, wherein the respiratory tract disorder is an allergen-inducedor inflammation-induced bronchial disorder.
 37. The method of claim 36,wherein the allergen-induced or inflammation-induced bronchial disorderis selected from the group consisting of bronchitis, obstructivebronchitis, spastic bronchitis, allergic bronchitis, allergic asthma,bronchial asthma, and COPD.
 38. The method of claim 35, wherein the PDEinhibitor and the β₂ adrenoceptor agonist are administeredsimultaneously.
 39. The method of claim 35, wherein the PDE inhibitorand the β₂ adrenoceptor agonist are administered more or lesssimultaneously.
 40. The method of claim 35, wherein the PDE inhibitorand the β₂ adrenoceptor agonist are administered in succession.
 41. Amethod of treating a respiratory tract disorder in a patient, comprisingadministering to said patient a therapeutically effective amount of thepharmaceutical composition as claimed in claim
 22. 42. The method ofclaim 41, wherein the respiratory tract disorder is an allergen-inducedor inflammation-induced bronchial disorder.
 43. The method of claim 42,wherein the allergen-induced or inflammation-induced bronchial disorderis selected from the group consisting of bronchitis, obstructivebronchitis, spastic bronchitis, allergic bronchitis, allergic asthma,bronchial asthma, and COPD.
 44. The method of claim 41, wherein the PDEinhibitor and the β₂ adrenoceptor agonist are administeredsimultaneously.
 45. The method of claim 41, wherein the PDE inhibitorand the β₂ adrenoceptor agonist are administered more or lesssimultaneously.
 46. The method of claim 41, wherein the PDE inhibitorand the β₂ adrenoceptor agonist are administered in succession.